1

Stroke accounts for 5 million deaths worldwide each year and is a leading cause of serious disability.1 Studies

have shown that the risk of death and unfavorable outcomes after the onset of stroke is very high. Currently, ≈33 million patients with stroke live worldwide, and a large proportion experience moderate or severe disability.2 For this reason, the global stroke-related burden is huge and continues to rise.3 Therefore, it is necessary to explore the predictors of poor prognosis after stroke.

Oxidized low-density lipoprotein (oxLDL) is a biomarker, which is significantly associated with atherosclerosis,4 and it has been designated as an independent risk factor in many acute or chronic inflammatory diseases.5 oxLDL can stimu-late peripheral leukocyte chemotaxis, platelet adhesion, and

aggregation, induce foam cell formation, and promote the development of atherosclerotic plaques.6,7 There have been many studies indicating that oxLDL is associated with an increased risk of cardiovascular disease8,9 and increased mortal-ity after acute myocardial infarction.10 The pathophysiological mechanisms of coronary and cerebrovascular atherosclerosis are considered to be similar. Moreover, atherosclerosis plays an important role in the occurrence and prognosis of ischemic stroke,11 so we hypothesize that oxLDL is also associated with the prognosis of ischemic stroke. Acute ischemic stroke is a heterogeneous disease with a variable pathogenesis,12 and so it is possible that oxLDL may be associated only with certain subtypes of stroke. However, to date, only limited research has been conducted on these relationships.

Background and Purpose—The association between oxidized low-density lipoprotein (oxLDL) and the long-term prognosis of stroke is unclear. The aim of this study is to investigate whether oxLDL levels contribute to the prognosis of stroke and stroke subtypes.

Methods—All patients with ischemic stroke were recruited from the SOS-Stroke (Study of Oxidative Stress in Patients With Acute Ischemic Stroke) and classified into 5 different subtypes, according to the TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment). We measured oxLDL levels and followed up with patients at 1 year after stroke onset. We analyzed the association between oxLDL and the clinical outcomes of death and poor functional outcome (modified Rankin Scale score of 3–6) of stroke and different stroke subtypes.

Results—Among the 3688 patients included in this study, 293 (7.94%) were deceased at the 1-year follow-up and 1020 (27.66%) had a poor functional outcome. Patients in the highest oxLDL quartile had a higher risk of 1-year stroke mortality (hazard ratio, 1.61; 95% confidence interval, 1.10–2.33; P<0.001) and a poor functional outcome (odds ratio, 1.48; 95% confidence interval, 1.15–1.89; P<0.001) compared with the lowest oxLDL quartile. In the subgroup analyses, oxLDL was only significantly associated with death and poor functional outcome in the large-artery atherosclerosis subgroup (P<0.05) and small-artery occlusion subgroup (P<0.05).

Conclusions—High levels of oxLDL were associated with the high risk of death and poor functional outcome within 1 year after stroke onset, especially in large-artery atherosclerosis and small-artery occlusion stroke subtypes. (Stroke. 2017;48:00-00. DOI: 10.1161/STROKEAHA.116.014816.)

Key Words: atherosclerosis ◼ lipoproteins ◼ oxidized low density lipoprotein ◼ prognosis ◼ stroke

Association of Oxidized Low-Density Lipoprotein With Prognosis of Stroke and Stroke Subtypes

Anxin Wang, PhD*; Yuling Yang, MD*; Zhaoping Su, MS; Wei Yue, MD; Hongjun Hao, MD; Lijie Ren, MD; Yongjun Wang, MD; Yibin Cao, MD; Yilong Wang, MD, PhD

Received July 20, 2016; final revision received September 18, 2016; accepted October 25, 2016.From the Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China (A.W., Yongjun Wang, Yilong Wang); China National

Clinical Research Center for Neurological Diseases, Beijing, China (A.W., Yongjun Wang, Yilong Wang); Center of Stroke, Beijing Institute for Brain Disorders, China (A.W., Yongjun Wang, Yilong Wang); Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, China (A.W., Yongjun Wang, Yilong Wang); Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China (A.W.); Departments of Neurology, Tangshan Gongren Hospital, China (Yuling Yang, Y.C.); Department of Epidemiology and Health Statistics, Academy of Public Health and Management, Weifang Medical University, China (Z.S.); Department of Neurology, Second Hospital of Tianjin Medical University, China (W.Y.); Department of Neurology, Tianjin Huanhu Hospital, China (W.Y.); Department of Neurology, Peking University First Hospital, Beijing, China (H.H.); and Department of Neurology, Shenzhen Second People’s Hospital, China (L.R.).

*Drs Wang and Yang contributed equally.The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.

116.014816/-/DC1.Correspondence to Yilong Wang, MD, PhD, No. 6 Tiantanxili, Dongcheng District, Beijing 100050, China. E-mail yilong528@gmail.com or Yibin Cao,

MD, No. 27 Wenhua Rd, Lubei District, Tangshan City, Hebei Province 063000, China. E-mail yibin07@sina.com© 2016 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.116.014816

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Therefore, in this prospective cohort study, we investigated the associations between oxLDL and the long-term prognosis of stroke and stroke subtypes.

Methods

Study Design and PopulationThe study population was recruited from the SOS-Stroke (Study on Oxidative Stress in Patients with Acute Ischemic Stroke ), a nation-wide multicenter prospective registry.13 The SOS-Stroke study enrolled 4164 consecutive patients with stroke from 43 designated hospitals in China from January to October 2014. Patients with a diagnosis of acute ischemic stroke within 7 days after the onset of stroke were included in this study. The inclusion criteria for SOS-Stroke were as follows: (1) age >18 years; (2) diagnosis of acute ischemic stroke by a neurologist and confirmation of such with brain computed tomography or magnetic resonance imaging; (3) time from onset of stroke to diagnosis was <1 week; and (4) the patient provided informed consent.

Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was sponsored by the China Stroke Prevention Project of the National Health and Family Planning Commission and was approved by the Ethics Committee of Beijing Tiantan Hospital, Xuanwu Hospital Capital Medical University, and Peking Union Medical College Hospital and was in compliance with the Declaration of Helsinki. All participants provided written informed consent.

Baseline Data Collection and Risk Factor DefinitionBaseline data on patient demographics and clinical characteristics (age, sex, marital status, alcohol use, education, and previous history of disease and medical treatments) were collected through face-to-face interviews undertaken by trained neurologists on admission. Alcohol use was defined as a daily alcohol intake of at least 100 mL for 3 days per week for >1 year. Physical activity was evaluated con-sidering the type and frequency of the activity. Previous history of diseases, including myocardial infarction, stroke, hypertension (his-tory of hypertension or antihypertensive medication use), diabetes mellitus (history of diabetes mellitus or hypoglycemic medications), hypercholesterolemia (history of dyslipidemia or lipid-lowering medication use), atrial fibrillation (confirmed by ECG on 1 occa-sion at least), and coronary artery disease, was determined through self-reporting.

Blood pressure was measured using a mercury sphygmomanom-eter with an appropriately sized cuff. We took 2 readings (5 minutes apart) of systolic blood pressure and diastolic blood pressure after participants had rested in a chair for at least 5 minutes, and we used the average of the 2 readings for our analysis. If the 2 measurements differed by >5 mm Hg, an additional reading was obtained, and we used the average of the 3 readings.

Biochemical IndicatorsBlood samples were obtained from the antecubital vein after an over-night fast from admission and transfused into vacuum tubes contain-ing ethylene diamine tetraacetic acid. Triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipopro-tein cholesterol (LDL-C), fasting blood glucose, high-sensitivity C-reactive protein, and other related laboratory indices were all mea-sured. All biochemical indicators, except oxLDL, were measured using a fully automatic biochemical analyzer (AU400; Olympus, Japan) at the central laboratories of the 43 designated hospitals in China.

oxLDL was measured in plasma samples obtained on the sec-ond day after admission using the oxLDL ELISA Kit (RapidBio Laboratory), according to the manufacturer’s guidelines. Samples were centrifuged within the same day as they were collected, at

2000g for 5 minutes, and the supernatant plasma samples were trans-ferred into polypropylene tubes at −80°C until being transported to Beijing from the 43 designated hospitals. oxLDL level was measured at the Central Neurology Laboratory (Laboratory of Immunology) of Peking University First Hospital.

The assay is a sandwich ELISA for the direct measurement of oxLDL in human EDTA-plasma. Standards and samples containing human oxLDL are added to wells of microplate coated with high-affinity antibodies. During the first incubation period, the antibodies immobilized on the wall of the microtiter wells capture the antigen in the patient samples. After washing away the unbound compo-nents from samples, a peroxidase-conjugated antibody is added to each microtiter well. Tetramethylbenzidine is used as a substrate for peroxidase. Finally, an acidic stop solution is added to terminate the reaction. The intensity of the yellow color is directly proportional to the oxLDL concentration of sample. A dose–response curve of absor-bance unit (optical density at 450 nm) versus concentration is gener-ated, using the values obtained from standard. oxLDL present in the patient samples is determined directly from this curve. The interas-say coefficients of variation is 1.10%. The intra-assay coefficients of variation is 1.24%.

Diagnosis of Stroke and Stroke Subtype ClassificationAcute ischemic stroke was diagnosed in accordance with the World Health Organization criteria14 and was confirmed using brain com-puted tomography or magnetic resonance imaging. The clinical diagnostic criteria for acute ischemic stroke were as follows: acute neurological functional deficit lasting longer than 24 hours and within 7 days of occurrence. Nonvascular events (including head trauma, primary and metastatic neoplasms, postseizure paralysis) that could lead to deficits in neurological function were excluded, and intracere-bral hemorrhage was excluded using computed tomography or mag-netic resonance imaging.

In accordance with the TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment),15 all patients with ischemic stroke were further classified into different stroke subtypes: large-artery athero-sclerosis (LAA), cardioembolism, small-artery occlusion (SAO), other determined etiology (SOE), and undetermined etiology. We performed electrocardiography, echocardiography, imaging of extra-cranial and intracranial arteries, computed tomography, magnetic resonance imaging, and laboratory assessments before any treatment. Classification of stroke subtype was based on the detailed review of patient’s clinical features and the results of diagnostic tests by 2 neu-rologists from each participating hospital. All the neurologists had rigorous unified training before they performed the classification criteria.

Clinical OutcomesWe followed up with all participants by telephone interview at 1 year after the initial stroke to assess the functional outcome and death. The functional outcome was measured by modified Rankin Scale, and the poor functional outcome was defined as a modified Rankin Scale score of 3 to 6. All causes of death were collected by a questionnaire. Based on a standardized interview protocol, the telephone follow-up was performed by specially trained interviewers.

Statistical AnalysisStatistical analysis was performed using a commercially available software program (SAS software version 9.3; SAS Institute Inc., Cary, NC). Continuous variables were described by means±SDs, and categorical variables were described as percentages. We used the Student t test or ANOVA to compare nonpaired samples of normally distributed parameters and the Wilcoxon or Kruskal–Wallis test for the comparison of nonparametric variables. The χ2 test was applied to compare categorical variables. We used multivariate logistic regres-sion to analyze the association between oxLDL and poor functional outcome of stroke and used Cox proportional-hazards modeling to

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calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of stroke mortality. Trend test was performed in the regression mod-els after the median oxLDL value of each quartiles was entered into the model and treated as a continuous variable. We further used these regression models to analyze the association between oxLDL and the prognosis of patients in each subtype of stroke. Because the number of participants in the SOE and undetermined etiology subtypes was small, we combined the 2 groups in the multivariate regression analy-sis models. Differences are statistically significant when P<0.05.

ResultsBaseline Characteristics of Study PatientsOf a total of 4164 individuals enrolled in the SOS-Stroke study, 24 subjects were excluded because of the nonavailabil-ity of oxLDL measurements, and 452 subjects were excluded because they were not available for follow-up. Consequently, a total of 3688 (1304; 35.36% men) patients were included in this study (Figure 1). Table I in the online-only Data Supplement shows the characteristics of patients with stroke, according to the inclusion and exclusion criteria in this study. Apart from alcohol use, tobacco use, and diastolic blood pres-sure, the characteristics of individuals excluded in this analy-sis were similar to those included (Table I in the online-only Data Supplement).

Table 1 provides demographic and baseline clinical char-acteristics of patients in different oxLDL groups. The mean age was 63.99±11.97 years. The mean plasma oxLDL con-centration was 56.83±20.89 μg/dL. The participants in this study were stratified into 4 groups, according to the plasma oxLDL quartiles: quartile 1, <48.09 μg/dL; quartile 2, 48.09 to 62.74 μg/dL; quartile 3, 62.75 to 70.17 μg/dL; and quar-tile 4, ≥70.18 μg/dL. The mean concentrations of oxLDL for these groups were 26.11±14.89, 57.26±3.99, 66.30±2.13, and 77.62±5.75 μg/dL, respectively.

There were significant differences in alcohol status, physi-cal activity, history of atrial fibrillation, antihypertensive use, and anticoagulant use between the different oxLDL groups (P<0.05). Participants in the high oxLDL group (quartile 4) were more likely to have a higher triglyceride level (P<0.01) and a lower HDL-C level (P<0.001). What is more, the cor-relation coefficient of HDL-C and oxLDL is −0.078, which

indicates that HDL-C levels is inversely correlated with oxLDL. The different oxLDL groups also differed signifi-cantly in terms of systolic blood pressure, baseline National Institutes of Health Stroke Scale, and LDL-C levels (P<0.05).

Association Between oxLDL and Prognosis of StrokeAmong the 3688 patients included in this study, 293 (7.94%) were deceased at the 1-year follow-up and 1020 (27.66%) had poor functional outcome (modified Rankin Scale score of 3–6). The univariable analyses of risk factors of poor prog-nosis of stroke are shown in Table II in the online-only Data Supplement. The multivariate logistic regression of associa-tions between oxLDL levels and poor functional outcome of stroke is shown in Table 2. Table 2 shows that patients with stroke with a high oxLDL level (quartile 4) had a significantly high risk of poor outcome of stroke at 1 year after stroke onset. After adjustment for potential confounding factors (age, sex, body mass index, current smoking habits, alcohol use, physical activity, level of education, history of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, myocardial infarc-tion, stroke, systolic blood pressure, diastolic blood pressure, blood glucose, National Institutes of Health Stroke Scale score on admission, triglyceride levels, LDL-C levels, HDL-C levels, and use of lipid-lowering drugs), the odds ratios for the association between the quartile 2, quartile 3, and quar-tile 4 subgroups and poor outcome of stroke at 1 year were 1.23 (95% CI, 0.96–1.58), 1.38 (95% CI, 1.08–1.76), and 1.48 (95% CI, 1.15–1.89), respectively (Table 3, model 4). Table 3 shows the multiple Cox regression analysis of associations between oxLDL levels and stroke mortality. After multivariate adjustment, the risk of death was significantly increased in the quartile 2, quartile 3, and quartile 4 groups, compared with the lowest oxLDL quartile (quartile 2: HR, 1.57; 95% CI, 1.06–2.32; quartile 3: HR, 1.80; 95% CI, 1.24–2.60; and quartile 4: HR, 1.61; 95% CI, 1.10–2.33), respectively (Table 3, model 4). Every increase in oxLDL levels, by 1 SD, was associated with a 23% increase in the risk of death and a 17% increase in the risk of poor outcome of stroke. Therefore, the risk of death and poor outcome of stroke significantly increased (P for trend <0.05) with increasing oxLDL levels (Tables 2 and 3).

Association Between oxLDL and Prognosis of Stroke, According to Stroke SubtypeTable III in the online-only Data Supplement shows the base-line characteristics of patients with different ischemic stroke subtypes. Figures 2 and 3 show the association of oxLDL lev-els with 1-year prognosis of stroke, according to the stroke subtype. We found that oxLDL levels were only significantly associated with poor outcome of stroke in the LAA subgroup (quartile 4: odds ratio, 1.41; 95% CI, 1.02–1.94) and the SAO subgroup (quartile 3: odds ratio, 1.66; 95% CI, 1.00–2.77; quartile 4: odds ratio, 2.04; 95% CI, 1.25–3.33), but not in the other subgroups (Figure 2). There was a similar relation-ship between oxLDL levels and stroke mortality in the LAA subgroup (quartile 3: HR, 1.71; 95% CI, 1.07–2.73; quartile 4: HR, 1.63; 95% CI, 1.01–2.65) and in the SAO subgroup (quartile 4: HR, 2.49; 95% CI, 1.02–6.11; Figure 3).

Figure 1. Flowchart of the study. CE indicates cardioembolism; LAA, large-artery atherosclerosis; oxLDL, oxidized low-density lipoprotein; SAO, small-artery occlusion; SOS-Stroke study (Study of Oxidative Stress in Patients With Acute Ischemic Stroke), and SOE and SUE: other determined etiology and unde-termined etiology.

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Table 1. Patient Baseline Characteristics, According to Quartiles of oxLDL Levels

Variable Total (n=3688)

Quartiles of oxLDL

P Value1st Quartile (n=924) 2nd Quartile (n=916) 3rd Quartile (n=923) 4th Quartile (n=925)

Age, y 63.99±11.97 63.35±11.78 63.89±12.16 64.92±11.85 63.81±12.04 0.08

Female, n (%) 1304 (35.36) 318 (34.42) 334 (36.46) 337 (36.51) 315 (34.05) 0.56

Body mass index, kg/m2, median (IQR)

24.22 (22.49–25.95) 24.22 (22.49–25.93) 24.22 (22.62–26.12) 24.22 (22.43–26.06) 24.22 (22.49–25.83) 0.19

Alcohol use, n (%) 272 (7.38) 76 (8.23) 100 (10.92) 60 (6.50) 36 (3.89) <0.001

Tobacco use, n (%) 457 (12.39) 109 (11.80) 143 (15.61) 105 (11.38) 100 (10.81) <0.01

Physical activity, n (%) 1365 (37.01) 360 (38.96) 384 (41.92) 311 (33.69) 310 (33.51) <0.001

Education level, n (%)

Illiteracy/primary 3338 (90.51) 839 (90.80) 826 (90.17) 831 (90.03) 842 (91.03) 0.86

Middle school and above 350 (9.49) 85 (9.20) 90 (9.83) 92 (9.97) 83 (8.97)

SBP, mm Hg 148.18±22.34 148.90±22.62 148.48±21.86 148.60±22.79 146.75±22.04 0.04

DBP, mm Hg 85.70±13.12 85.60±12.78 86.06±13.37 85.93±13.09 85.20±13.22 0.09

FBG, mmol/L 6.51±2.80 6.59±3.04 6.46±2.79 6.52±2.70 6.48±2.67 0.50

TC, mmol/L 4.60±1.41 4.56±1.58 4.60±1.17 4.68±1.35 4.57±1.50 0.26

TG, mmol/L 1.76±1.30 1.78±1.47 1.71±1.15 1.68±1.17 1.89±1.38 <0.01

HDL-C, mmol/L 1.16±0.40 1.20±0.38 1.16±0.45 1.16±0.40 1.14±0.35 <0.001

LDL-C, mmol/L 2.85±1.30 2.79±1.38 2.83±1.66 2.93±1.04 2.85±1.03 <0.001

NIHSS on admission, median (IQR)

4 (2–8) 3 (2–6) 4 (2–8) 5 (2–8) 5 (2–8) <0.001

History of disease, n (%)

Diabetes mellitus 862 (23.37) 222 (24.03) 217 (23.69) 216 (23.40) 207 (22.38) 0.85

Hypertension 2432 (65.94) 601 (65.04) 595 (64.96) 624 (67.61) 612 (66.16) 0.60

Dyslipidemia 394 (10.68) 92 (9.96) 99 (10.81) 114 (12.35) 89 (9.62) 0.23

Stroke 832 (22.56) 202 (21.86) 212 (23.14) 225 (24.38) 193 (20.86) 0.30

Myocardial infarction 85 (2.30) 21 (2.27) 27 (2.95) 15 (1.63) 22 (2.38) 0.31

Atrial fibrillation 211 (5.72) 38 (4.11) 49 (5.35) 64 (6.93) 60 (6.49) 0.04

Medications during hospitalization, n (%)

Hypoglycemic 722 (19.58) 191 (20.67) 170 (18.56) 188 (20.37) 173 (18.70) 0.55

Antihypertensive 1739 (47.15) 440 (47.62) 406 (44.32) 410 (44.42) 483 (52.22) <0.01

Lipid-lowering drugs 3325 (90.16) 846 (91.56) 814 (88.86) 836 (90.57) 829 (89.62) 0.24

Antiplatelet 3401 (92.22) 860 (93.07) 841 (91.81) 861 (93.28) 839 (90.70) 0.13

Anticoagulation 345 (9.35) 58 (6.28) 100 (10.92) 94 (10.18) 93 (10.05) <0.01

Subtype of stroke, n (%)

Large-artery atherosclerosis

2113 (57.29) 544 (58.87) 529 (57.75) 550 (59.59) 490 (52.97) 0.03

Cardioembolism 226 (6.13) 39 (4.22) 60 (6.55) 56 (6.07) 71 (7.68) …

Small-artery occlusion 1170 (31.72) 296 (32.03) 281 (30.68) 271 (29.36) 322 (34.81) …

Other or undetermined 66 (1.79) 16 (1.73) 16 (1.75) 22 (2.38) 12 (1.30) …

Unknown 113 (3.06) 29 (3.14) 30 (3.28) 24 (2.60) 30 (3.24) …

DBP indicates diastolic blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; NIHSS, National Institutes of Health Stroke Scale; oxLDL, oxidized low-density lipoprotein; SBP, systolic blood pressure; TC, total cholesterol; and TG, triglyceride.

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DiscussionIn this multicenter prospective registry study, we found that high oxLDL levels were associated with the high risk of death and poor outcome within 1 year after the onset of stroke. The results further demonstrate that higher oxLDL levels were particularly related to death and poor outcome in the LAA and SAO stroke subtypes, but not in the cardioembolism and other stroke subtypes.

Studies investigating the relationship between oxLDL lev-els and the prognosis of stroke are rare. Our findings are con-firmed and extended previous studies. Guldiken et al16 found that circulating oxLDL levels were increased in the patients of acute ischemic stroke. Tsai et al17 demonstrated that oxidative stress was progressive after ischemic stroke and contributed to further neurological damage. Furthermore, another study revealed that higher plasma oxLDL levels were a predictor for poor prognosis 3 months after acute ischemic stroke, even after adjustments for high-sensitivity C-reactive protein, white blood cell, infarct volume, and other lipid confounders and traditional risk factors for stroke outcome.18 The authors sug-gested that a 1-U/mL increase in oxLDL levels would increase

the rate of poor outcome by 9%. Similarly, our results suggest that an increase of 1 SD in oxLDL levels would increase the poor functional outcome rate by 17% and mortality by 23% 1 year after acute ischemic stroke.

The mechanism underlying this positive association between oxLDL levels and prognosis of stroke is unclear. Previous researches suggested that the potential mechanism may involve the following. It is believed that inflammation, an important early stage of endothelial dysfunction, is a key ini-tiating step in the development of atherosclerosis. The LDL-C particles trapped in the subendothelial space are mildly oxi-dized by resident vascular cells in circulation, and the oxLDL induce leukocyte–endothelial cell adhesion, which is likely the consequence of an increased expression of inflammatory markers. Moreover, oxLDL activates cell surface receptors on monocytes, macrophages, and vascular smooth muscle cells, which sequentially promotes endothelial dysfunction and causes acute inflammatory responses. This process plays a key role in the progression of atherosclerosis. Furthermore, completely oxLDL can be recognized by scavenger receptors on macrophages and internalized to form foam cells, which

Table 2. Odds Ratio (95% Confidence Intervals) for Poor Outcomes, According to Quartiles of Plasma oxLDL Levels, in the SOS-Stroke Study (Study of Oxidative Stress in Patients With Acute Ischemic Stroke)

oxLDL Quartile

P for Trend Per SD IncreaseQuartile 1 Quartile 2 Quartile 3 Quartile 4

No. of events 184 (18.04%) 255 (25.00%) 291 (28.53%) 290 (28.43%) … …

Model 1* 1 1.55 (1.25–1.93) 1.85 (1.50–2.29) 1.84 (1.48–2.27) <0.001 1.31 (1.21–1.42)

Model 2† 1 1.54 (1.23–1.92) 1.78 (1.43–2.21) 1.85 (1.49–2.30) <0.001 1.31 (1.21–1.42)

Model 3‡ 1 1.25 (0.98–1.61) 1.40 (1.10–1.79) 1.49 (1.17–1.91) <0.001 1.18 (1.08–1.29)

Model 4§ 1 1.23 (0.96–1.58) 1.38 (1.08–1.76) 1.48 (1.15–1.89) <0.001 1.17 (1.07–1.28)

oxLDL indicates oxidized low-density lipoprotein.*Unadjusted.†Adjusted for age and sex.‡Adjusted for age, sex, body mass index, current smoking habits, alcohol use, physical activity, level of education, history of stroke, hypertension, diabetes mellitus,

hyperlipidemia, atrial fibrillation, myocardial infarction, blood glucose, systolic blood pressure, diastolic blood pressure, National Institutes of Health Stroke Scale score on admission.

§Adjusted for variables in model 3 plus hyperlipidemia, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and lipid-lowering drugs.

Table 3. Hazard Ratios (95% Confidence Intervals) for Stroke Mortality, According to Quartiles of Plasma oxLDL Levels, in the SOS-Stroke Study (Study of Oxidative Stress in Patients With Acute Ischemic Stroke)

oxLDL Quartile

P for Trend Per SD IncreaseQuartile 1 Quartile 2 Quartile 3 Quartile 4

No. of events 42 (14.33%) 70 (23.89%) 93 (31.74%) 88 (30.03%) … …

Model 1* 1 1.60 (1.09–2.35) 2.07 (1.44–2.98) 2.04 (1.41–2.95) <0.001 1.38 (1.20–1.58)

Model 2† 1 1.59 (1.08–2.33) 1.91 (1.33–2.76) 2.05 (1.42–2.96) <0.001 1.38 (1.19–1.58)

Model 3‡ 1 1.62 (1.10–2.40) 1.82 (1.26–2.62) 1.64 (1.13–2.38) 0.01 1.25 (1.08–1.44)

Model 4§ 1 1.57 (1.06–2.32) 1.80 (1.24–2.60) 1.61 (1.10–2.33) 0.02 1.23 (1.06–1.42)

oxLDL indicates oxidized low-density lipoprotein.*Unadjusted.†Adjusted for age and sex.‡Adjusted for age, sex, body mass index, current smoking habits, alcohol use, physical activity, level of education, history of stroke, hypertension, diabetes mellitus,

hyperlipidemia, atrial fibrillation, myocardial infarction, blood glucose, systolic blood pressure, diastolic blood pressure, National Institutes of Health Stroke Scale score on admission.

§Adjusted for variables in model 3 plus hyperlipidemia, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and lipid-lowering drugs.

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is the important hallmark of the atherosclerotic lesion. This process plays a key role in the development of atherosclero-sis. Atherosclerosis not only plays an important role in the occurrence of stroke but also has an effect on stroke prognosis. Ovesen et al19 have shown that intracranial atherosclerosis is related to stroke outcomes in the total patient population with ischemic stroke. In addition, endothelial cells itself is related to clinical outcome of stroke.20,21 As mentioned above, oxLDL can induce and promote endothelial dysfunction. When endothelial cells were triggered, it can express adhesion and chemotactic molecules and acquire a permeability to macromolecules, these will cause the composition of the subendothelial extra-cellular matrix is modified. Hence, endothelial repair has a bad effect on the recovery of the ischemic penumbra.22 In light of these, oxLDL levels may represent a modifiable risk factor that has an effect on mortality and poor outcomes of stroke. What is more, we also found that HDL-C levels is inversely correlated

with oxLDL. The potential mechanism was as follows. HDL-C is known to have its antiatherogenic effect by inducing reverse cholesterol transport,23 which can enter into the intima; it reverses the oxLDL-induced impaired endothelium-dependent vasodilation via removing Lysophosphatidylcholine from oxLDL and preventing lysophosphatidylcholine from inhibit-ing the endothelium-dependent vasodilation. Besides, HDL-C also can inhibit LDL-C oxidation probably through their para-oxonase-1 content24 and apo AI.25

Another important finding in our study was that oxLDL was particularly related to death and poor outcome in the stroke subtypes of LAA and SAO. oxLDL has different con-sequences in different subtypes of ischemic stroke, as a result of their heterogeneous pathogenesis. The major pathogen-esis of LAA-type stroke is atherothrombosis,26 and therefore, increased oxLDL levels in patients with LAA-type stroke may be related to poor stroke outcomes via the previously men-tioned mechanisms. The pathogenesis of SAO-type stroke is lipohyalinosis,27 as a consequence of enhanced small-vessel permeability of the blood–brain barrier.28 Endothelial dys-function and oxidative stress are important factors contribut-ing to the small-vessel permeability.17 Given its role in causing endothelial dysfunction, oxidative stress, and atherosclerosis, oxLDL clearly contributes to the pathogenesis and prognosis of SAO-type stroke as well.

The present study has some limitations. First, the num-bers of the cardioembolism and other stroke subtypes in our study were small, which may decrease the statistical power of our study to detect the association between oxLDL levels and death and poor outcome in these stroke subtypes. Second, oxLDL levels during the follow-up period were not recorded in this study, and so we could not evaluate changes in plasma oxLDL levels and their impact on stroke prognosis over time. Third, we also did not record plasma oxLDL level in patients at the arrival at hospital, so we could not investigate the poten-tial difference between acute and postacute levels of oxLDL. Therefore, further research is needed to provide insight into the important role that oxLDL level and its variability plays in the prognosis of ischemic stroke and the potential difference between acute and postacute levels of oxLDL.

ConclusionsOur study provides evidence that high levels of oxLDL were associated with the high risk of death and poor outcome within 1 year after the onset of stroke, especially in the LAA and SAO stroke subtypes. It is needed further larger study to confirm our findings.

AcknowledgmentsWe gratefully acknowledge all of the 43 participating hospitals and the clinicians, statisticians, and imaging and laboratory technicians.

Sources of FundingThis study was supported by the China Stroke Prevention Project of the National Health and Family Planning Commission.

DisclosuresNone.

Figure 2. Odds ratio (OR, 95% confidence intervals [CIs]) for poor functional outcomes in different stroke subtypes, according to quartiles of plasma oxidized low-density lipoprotein (oxLDL) levels, in the SOS-Stroke study (Study of Oxidative Stress in Patients With Acute Ischemic Stroke).

Figure 3. Hazard ratio (HR; 95% confidence intervals [CIs]) for stroke mortality in different stroke subtypes, according to quar-tiles of plasma oxidized low-density lipoprotein (oxLDL) levels, in the SOS-Stroke study (Study of Oxidative Stress in Patients With Acute Ischemic Stroke).

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Yibin Cao and Yilong WangAnxin Wang, Yuling Yang, Zhaoping Su, Wei Yue, Hongjun Hao, Lijie Ren, Yongjun Wang,

SubtypesAssociation of Oxidized Low-Density Lipoprotein With Prognosis of Stroke and Stroke

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1

SUPPLEMENTAL MATERIAL

Supplemental Tables

Table I. Characteristics of patients with stroke, according to the inclusion and exclusion

criteria

Variable Patients included

(n=3688)

Patients excluded

(n=476) p value

Age, years 63.99±11.97 63.48±13.00 0.59

Female, n(%) 1304(35.36) 158(33.19) 0.35

Body mass index (kg/m2),

median (IQR) 24.22(22.49-25.95) 24.22(22.50-25.64) 0.09

Alcohol use, n(%) 272(7.38) 135(28.36) <0.001

Tobacco use, n(%) 457(12.39) 186(39.08) <0.001

Physical activity, n(%) 1365(37.01) 184(38.66) 0.48

Education level, n (%)

Illiteracy/primary 3338(90.51) 435(91.39) 0.54

Middle school and above 350(9.49) 41(8.61)

SBP, mmHg 148.18±22.34 145.89±22.65 0.06

DBP, mmHg 85.70±13.12 84.30±13.81 <0.01

FBG, mmol/l 6.51±2.80 6.60±2.77 0.72

TC, mmol/l 4.60±1.41 4.58±1.37 0.65

TG, mmol/l 1.76±1.30 1.61±1.04 0.02

HDL-C, mmol/l 1.16±0.40 1.18±0.40 0.75

LDL-C, mmol/l 2.85±1.30 2.86±1.08 0.97

NIHSS on admission,

median(IQR) 4(2-8) 4(2-8) 0.94

History of disease, n(%)

Diabetes 862(23.37) 110(23.11) 0.90

Stroke 832(22.56) 110(23.11) 0.79

Hypertension 2432(65.94) 310(65.12) 0.72

Dyslipidemia 394(10.68) 49(10.29) 0.80

Myocardial infarction 85(2.30) 12(2.52) 0.77

Atrial fibrillation 211(5.72) 30(6.30) 0.61

Subtype of stroke, n(%)

Large-artery atherosclerosis 2113(57.29) 273(57.35) 0.55

Cardioembolism 226(6.13) 34(7.14)

Small-artery occlusion 1170(31.72) 141(29.62)

Other or undetermined 66(1.79) 8(1.68)

Unknown 113(3.06) 20(4.20)

IQR: interquartile range; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG:

fasting blood glucose; TG: triglyceride; TC: total cholesterol; HDL-C: high-density

lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; NIHSS: National

Institutes of Health Stroke Scale.

2

Table II. Characteristics of patients with stroke, according to 1-year outcomes

Variable

Death

Poor Outcome

Yes (N=293) No (N=3395) p

value Yes (N=1020) No (N=2668)

p

value

Age, years 71.35±11.54 63.36±11.79 <0.001 68.22±11.72 62.38±11.66 <0.001

Female, n(%) 118(40.27) 1186(34.93) 0.07 404(39.61) 900(33.73) <0.001

Body mass index (kg/m2), median

(IQR) 23.87(21.47-25.35) 24.22(22.58-26.03) <0.001 24.22(22.07-25.71) 24.22(22.60-26.07) <0.001

Alcohol use, n(%) 1(0.34) 271(7.98) <0.001 52(5.10) 220(8.25) <0.001

Tobacco use, n(%) 2(0.68) 455(13.40) <0.001 80(7.84) 377(14.13) <0.001

Physical activity, n(%) 86(29.35) 1279(37.67) <0.01 335(32.84) 1030(38.61) 0.001

Education level, n (%)

Illiteracy/primary 272(92.83) 3066(90.31) 0.16 947(92.84) 2391(89.62) <0.01

Middle school and above 21(7.17) 329(9.69) 73(7.16) 277(10.38)

SBP, mmHg 150.17±24.20 48.01±22.17 0.13 150.60±23.55 147.26±21.79 <0.001

DBP, mmHg 85.20±14.47 85.74±13.00 0.85 85.46±13.72 85.79±12.88 0.70

FBG, mmol/l 7.03±3.04 6.47±2.78 <0.001 6.74±2.92 6.43±2.75 <0.001

TC, mmol/l 4.56±1.20 4.61±1.42 0.49 4.59±1.30 4.61±1.45 0.89

TG, mmol/l 1.54±1.06 1.78±1.32 <0.001 1.64±1.14 1.81±1.36 <0.001

HDL-C, mmol/l 1.14±0.34 1.16±0.40 0.71 1.16±0.38 1.16±0.40 0.67

LDL-C, mmol/l 2.84±0.98 2.85±1.33 0.97 2.85±0.96 2.85±1.41 0.39

NIHSS on admission, median(IQR) 9(5-16) 4(2-7) <0.001 8(5-13) 3(2-6) <0.001

History of disease, n(%)

Diabetes 71(24.23) 791(23.30) 0.72 265(25.98) 597(22.38) 0.02

Hypertension 193(65.87) 2239(65.95) 0.98 700(68.63) 1732(64.92) 0.03

Dyslipidemia 22(7.51) 372(10.96) 0.07 102(10.00) 292(10.94) 0.41

Stroke 88(30.03) 744(21.91) <0.01 303(29.71) 529(19.83) <0.001

Myocardial infarction 10(3.41) 75(2.21) 0.19 27(2.65) 58(2.17) 0.39

Atrial fibrillation 42(14.33) 169(4.98) <0.001 94(9.22) 117(4.39) <0.001

3

Medications during hospitalization,

n(%)

Hypoglycemic 53(18.09) 669(19.71) 0.50 202(19.80) 520(19.49) 0.83

Antihypertensive 136(46.42) 1603(47.22) 0.79 484(47.45) 1255(47.04) 0.82

Statins 240(81.91) 3085(90.87) <0.001 878(86.08) 2447(91.72) <0.001

Antiplatelet 251(85.67) 3150(92.78) <0.001 898(89.35) 2418(93.50) <0.001

Anticoagulation 39(13.31) 306(9.01) 0.02 126(12.54) 202(7.81) <0.001

oxLDL(ug/dl) 62.56±16.17 56.33±21.18 <0.001 60.58±17.92 55.39±21.75 <0.001

IQR: interquartile range; oxLDL: oxidized low-density lipoprotein; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting

blood glucose; TG: triglyceride; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol;

NIHSS: National Institutes of Health Stroke Scale.

4

TableⅢ. Baseline characteristics of patients with different ischemic stroke subtypes

Variable LAA (N=2113) CE (N=226) SAO (N=1170) SOE & SUE (N=179) p value

Age, years 64.63±11.46 68.37±12.65 62.70±11.69 59.36±15.67 <0.001

Female, n(%) 725(34.31) 106(46.90) 411(35.13) 62(34.64) <0.01

Body mass index (kg/m2),

median (IQR) 24.22(22.49-25.95) 24.22(22.10-25.39) 24.29(22.59-26.12) 24.22(22.09-25.39) <0.01

Alcohol use, n(%) 161(7.62) 7(3.10) 90(7.69) 14(7.82) 0.09

Tobacco use, n(%) 263(12.45) 12(5.31) 164(14.02) 18(10.06) <0.01

Physical activity, n(%) 811(38.38) 60(26.55) 445(38.03) 49(27.37) <0.001

Education level, n (%)

Illiteracy/primary 1906(90.20) 205(90.71) 1085(92.74) 142(79.33) <0.001

Middle school and above 207(9.80) 21(9.29) 85(7.26) 37(20.67)

SBP, mmHg 148.68±21.80 143.12±23.12 149.07±22.79 142.82±23.29 <0.001

DBP, mmHg 85.64±12.79 83.23±14.48 86.73±13.38 82.77±12.61 <0.001

FBG, mmol/l 6.52±2.75 6.35±2.32 6.54±2.90 6.43±3.30 0.22

TC, mmol/l 4.63±1.43 4.32±1.20 4.65±1.40 4.37±1.41 <0.001

TG, mmol/l 1.75 ±1.28 1.61±1.24 1.84±1.36 1.69±1.94 <0.001

HDL-C, mmol/l 1.14±0.38 1.20±0.37 1.19±0.43 1.09±0.31 <0.001

LDL-C, mmol/l 2.89±1.22 2.65±0.89 2.83±1.28 2.80±2.37 <0.001

NIHSS on admission,

median(IQR) 5(2-8) 8(3-15) 3(2-6) 4(2-9) <0.001

History of disease, n(%)

Diabetes 526(24.89) 33(14.60) 271(23.16) 32(17.88) <0.01

Hypertension 1454(68.81) 133(58.85) 777(66.41) 68(37.99) <0.001

Dyslipidemia 244(11.55) 13(5.75) 128(10.94) 9(5.03) <0.001

Stroke 493(23.33) 46(20.35) 271(23.16) 22(12.29) <0.001

Myocardial infarction 44(2.08) 10(4.42) 29(2.48) 2(1.12) 0.10

Atrial fibrillation 51(2.41) 142(62.83) 14(1.20) 4(2.23) <0.001

Medications during

5

hospitalization, n(%)

Hypoglycemic 444(21.01) 27(11.95) 222(18.97) 29(16.20) <0.01

Antihypertensive 970(45.91) 119(52.65) 572(48.89) 78(43.58) 0.09

Lipid-lowering drugs 1948(92.19) 173(76.55) 1057(90.34) 147(82.12) <0.001

Antiplatelet 1985(93.94) 146(64.60) 1109(94.79) 161(89.940 <0.001

Anticoagulation 172(8.14) 99(43.81) 59(5.04) 15(8.38) <0.001

oxLDL(ug/dl) 56.40±20.45 60.57±19.16 57.02±21.82 55.86±21.48 0.01

LAA: large-artery atherosclerosis; CE: cardioembolism; SAO: small-artery occlusion; SOE & SUE: other determined etiology and undetermined

etiology; IQR: interquartile range; oxLDL: oxidized low-density lipoprotein; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG:

fasting blood glucose; TG: triglyceride; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein

cholesterol; NIHSS: National Institutes of Health Stroke Scale.